The rapid reuptake of the monoaminergic neurotransmitters, dopamine (DA), serotonin (5-HT), and norepinephrine (NE) is described as the terminal step in the synaptic signaling of these neurotransmitters. The reuptake of DA, 5-HT and NE into the pre-synaptic cleft is mediated by the dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET), respectively. Inhibition of DA reuptake is proposed to be the underlying mechanism of abused drugs such as cocaine and methamphetamine. Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) has also been shown to inhibit DA reuptake, albeit with no evidence to its abuse liability in humans, despite preclinical data that suggests cocaine-like subjective effects [1] (and references cited therein). Based on its interesting pharmacological profile, modafinil and particularly its R-enantiomer (Armodafinil) have drawn recent attention focused on its binding mode at the DAT [1, 2]. These studies independently demonstrated that modafinil binds the DAT in a unique fashion as compared to cocaine and suggests that this may be related to its behavioral profile. There are many reports suggesting additional mechanisms underlying the pharmacological actions of modafinil and in particular its effectiveness in animal models of drug seeking [3-7]. However, direct interaction with these other targets has not been demonstrated. One potential confound is that modafinil is a non-aminergic compound with limited water solubility, which can complicate investigation due to the large concentration of drug needed for in vitro and in vivo studies. Direct or downstream interactions of modafinil with numerous targets including histaminergic, GABAergic, orexinergic, glutamatergic, adrenergic and serotonergic neurons have been reported [6, 7]. However, whether or not these targets are related to clinical efficacy remains undetermined.
Recently, a series of modafinil analogs have been synthesized and evaluated for binding at DAT, SERT, and NET [8]. Structure-activity relationship (SAR) studies suggested binding interactions at the DAT that appeared to contrast with cocaine and to be more similar to the atypical dopamine uptake inhibitor class of benztropine analogs, which also have a biphenyl structural motif [9]. However, the binding mode of the non-tropane based modafinil and its analogues appear to be unique at the DAT and may be exploited toward efficacious therapeutics without abuse liability. Thus, there remains a need in the art for compounds with improved monoamine transporter affinity(ies) with enhanced solubility properties that will allow further investigation into novel mechanisms that may lead to therapeutic benefit over currently used monoamine transport inhibitors.